Compounds and methods for treatment of inflammatory bowel disease with extra-intestinal manifestations

ABSTRACT

The present invention relates to, inter alia, methods of treatment and combinations of (R)-2-(7-(4-cyclopentyl-3-(triflu-oromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) useful for the treatment of extra-intestinal manifestations (EIM) in an individual with inflammatory bowel disease (BBD) and for the treatment of pyoderma gangrenosum (PG). In some embodiments, the methods further comprise administering Compound 1, or a harmaceutically salt, solvate, or hydrate thereof, in combination with a therapeutically effective amount of a compound selected from the group consisting of: a corticosteroid, a 5-aminosalicylic acid derivative, and a TNF-alpha inhibitor; or a corticosteroid, an immunosuppressant, a biologic, an anti-inflammatory agent, and an antibiotic.

FIELD OF THE INVENTION

The present invention relates to, inter alia, methods of treatment andcombinations of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1) useful for the treatment of extra-intestinalmanifestations (EIM) in an individual with inflammatory bowel disease(IBD) and for the treatment of pyoderma gangrenosum (PG). In someembodiments, the methods further comprise administering Compound 1, or apharmaceutically salt, solvate, or hydrate thereof, in combination witha therapeutically effective amount of a compound selected from the groupconsisting of: a corticosteroid, a 5-aminosalicylic acid derivative, anda TNF-alpha inhibitor; or a corticosteroid, an immunosuppressant, abiologic, an anti-inflammatory agent, and an antibiotic.

BACKGROUND OF THE INVENTION

The sphingosine-1-phosphate (SIP) receptors 1-5 constitute a family of Gprotein-coupled receptors with a seven-transmembrane domain. Thesereceptors, referred to as S1P₁, to S1P₅ (formerly termed endothelialdifferentiation gene (EDG) receptor-1, -5, -3, -6, and -8, respectively;Chun et. al., Pharmacological Reviews, 54:265-269, 2002), are activatedvia binding by sphingosine-1-phosphate, which is produced by thesphingosine kinase-catalyzed phosphorylation of sphingosine. SiP₁, S1P₄,and S1P₅ receptors activate Gi but not Gq, whereas S1P₂ and S1P₃receptors activate both Gi and Gq. The S1P₃ receptor, but not the S1P₁receptor, responds to an agonist with an increase in intracellularcalcium.

The compound(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1) is a potent (EC₅₀ cAMP, 0.093 nM (human)) andselective (EC₅₀ β-arrestin, 6.10 nM (S1P₁), >10,000 nM (S1P₂), >10,000nM, (S1P₃), 147 nM (S1P₄), and 24.4 nM (S1P₅)), orally availableinvestigational drug candidate for the S1P₁ receptor.

In preclinical studies, Compound 1 showed calculated lymphocyte loweringIC₅₀ values in four different species: 0.101 μM (mouse), 0.051 μM (rat),0.058 μM (dog), and 0.098 μM (monkey). Notably, the calculatedlymphocyte lowering IC₅₀ values reflect total plasma concentrationwherein Compound 1 is highly protein bound (97.8% human, 98.0% rat).Compound 1 was shown to be efficacious in the murine experimentalautoimmune encephalomyelitis (EAE) model that mimics multiple sclerosis.Prophylactically, Compound 1 prevented the onset and severity of diseaserelative to vehicle up to day 25, at which time dosing was discontinued.All treatment arms went on to develop severe disease. Therapeuticadministration of Compound 1 was also examined. Treatment began at day18, by which time all animals had developed severe disease. Compound 1was administered from day 18 to day 37 and showed to reverse the diseaserelative to vehicle and was similar to the efficacy observed withfingolimod (i.e., GILENYA® was approved in September 2010 for thetreatment of individuals with relapsing forms of multiple sclerosis).Similarly, Compound 1 was efficacious in a collagen induced arthritis(CIA) model. Prophylactic oral administration in female Lewis ratsresulted in a significant reduction in ankle diameters on day 17following a daily oral dose and was similar to that observed in ratstreated with fingolimod or methotrexate. Improvement in histologicalparameters in the knees and ankles of CIA rats was also observed,suggesting that inhibiting lymphocyte entry into arthritic joints withCompound 1 treatment suppresses CIA in rodents. Additional details canbe found in the following, PCT application, serial numberPCT/US2009/004265, filed 22 Jul. 2009 (International Publication NumberWO2010/011316); PCT application, serial number PCT/US2011/000153, filed27 Jan. 2011 (International Publication Number WO2011/094008); andBuzard: D. J., et. al., ACS Med. Chem. Lett. 2014, 5, 1313-1317; eachhereby incorporated by reference in its entirety.

S1P is a signaling sphingolipid required by lymphocytes to exit thelymphoid tissue and enter the bloodstream via a chemotactic gradient.The S1P1 receptor is a physiological mediator which has been shown toregulate lymphocyte recirculation between lymphoid tissue and blood.Binding and internalization of the S1P1 receptor may result inlymphocyte retention within lymphoid tissue, with subsequent reductionin peripheral lymphocyte count and lymphocyte availability forrecruitment to sites of inflammation. S1P1 receptor surface expressionis required for S1P gradient-mediated lymphocyte migration out oflymphoid tissue into the circulation (Brinkmann V., Nat Rev Drug Discov2010 November; 9(11):883-97).

Compound 1 is an orally available, selective, sphingosine 1-phosphatereceptor (S1P) agonist. The S1P1 receptor is a physiological mediatorwhich has been shown to regulate lymphocyte recirculation betweenlymphoid tissue and blood. Binding and internalization of the S1P1receptor may result in lymphocyte retention within lymphoid tissue, withsubsequent reduction in peripheral lymphocyte count and lymphocyteavailability for recruitment to sites of inflammation. S1P1 receptorsurface expression is required for S1P gradient-mediated lymphocytemigration out of lymphoid tissue into the circulation (Brinkmann V., et.al., Nat Rev Drug Discov 2010 November; 9 (11):883-97).

Compound 1 is being developed to treat autoimmune diseases. Initialinvestigations will focus on Inflammatory Bowel Disease (IBD), which isa broad term that describes conditions with chronic or recurring immuneresponse and inflammation of the gastrointestinal tract (Centers forDisease Control and Prevention. Inflammatory bowel disease (IBD).http://www.cdc.gov/ibd/. Accessed Jan. 8, 2015). There are two majortypes of IBD: Crohn's disease (CD) and ulcerative colitis (UC). Theseare chronic remittent or progressive inflammatory conditions that mayaffect the entire gastrointestinal tract (CD) and the colonic mucosa(UC), and are associated with an increased risk for colon cancer. 11Collectively, individuals with IBD suffer.from a multitude of GIsymptoms, including diarrhea, rectal bleeding and abdominal pain.

The causes of these IBDs are not completely understood, but threecharacteristics define their etiology: (1) genetic predisposition; (2)an altered, dysregulated immune response; and (3) an altered response togut microorganisms. 2 The triggering event for the activation of theimmune response in IBD has yet to be identified, but possible factorsrelated to this event include a pathogenic organism (as yetunidentified) or an inappropriate response to a normally innocuousmicrobial or other antigen (perhaps due to failure to downgrade theinflammatory response, and/or to repeated exposure to such antigen froman alteration in barrier function) (Centers for Disease Control andPrevention. Inflammatory bowel disease (IBD). http://www.cdc.gov/ibd/.Accessed Jan. 8, 2015). Once the inflammation has been triggered, it maybe difficult for the IBD individual's immune system to turn off theresponse (Danese S. and Fiocchi C., N Engl J Med. 2011 November; 365;18:1713-1725).

The number of individuals diagnosed with IBD has dramatically increasedworldwide over the past 50 years.5 In 2014, The Crohn's and ColitisFoundation of American estimated that approximately 1.6 million peopleare affected by IBD in the United States (US) alone, (Crohn's andColitis Foundation of America. The Facts About Inflammatory BowelDiseases. November 2014, New York, N.Y. 10017.http://www.ccfa.org/assets/pdfs/ibdfactbook.pdf. Accessed Jan. 7, 2015)with as many as 70,000 new cases diagnosed in the US each year (LoftusE. V., Gastroenterology, 2004; 126:1504-17). In Europe, an estimated2.5-3 million people are affected by IBD, (Burisch J, et. al., J CrohnsColitis. 2013 May; 7(4):322-37) and as many as 5 million may be affectedworldwide (World IBD Day. http://www.worldibdday.org/index.html.Accessed Jan. 7, 2015). Universally, incidence rates for both Crohn'sdisease and ulcerative colitis were highest among individuals between 20and 40 years old. Thus, IBD affects individuals in the healthiest andproductive years of life, resulting in long-term cost to the individual,health-care system and society (American Gastroenterological Assoc. IBDemerges as a global disease, 2012 Jan. 5, ScienceDaily.www.sciencedaily.com/releases/2012/01/120104135402.htm. Accessed Jan. 7,2015).

Treatment for individuals with IBD is generally for symptomatic care(relief of symptoms) and mucosal healing and includes 5 major classes ofmedications: aminosalicylates (5-ASA), antibiotics, corticosteroids,immunomodulators, and biologic therapies. These drugs are generallyprescribed in a “step-up” approach, with escalation of the medicalregimen until a response is achieved (Medscape. Inflammatory BowelDisease: Practice Essentials.http://emedicine.medscape.com/article/179037-overview#aw2aab6b2b4.Accessed Jan. 8, 2015).

A single ascending dose study and a multiple ascending dose study,conducted in healthy subjects, have demonstrated the lymphocyte loweringcapabilities of Compound 1. Lymphocyte trafficking agents such asnatalizumab and vedolizumab, both injectable or infused therapies, havedemonstrated efficacy in IBD indications. More recently, ozanimod, anS1P1 oral receptor modulator showed promising results in a Phase 2 studyfor UC. The availability of oral lymphocyte trafficking agents such asCompound 1 would offer individuals an additional, more convenienttreatment for IBD.

Inflammatory bowel diseases are associated with various extra-intestinalmanifestations (EIMs). The prevalence of IBD with EIMs as co-morbiditiesvaries from 25% to 40% depending on the clinical presentation (TaverelaV. F., Aliment Pharmacol Ther 2004; Suppl 4:50-53). Specifically, IBDwith EIMs could have a negative impact on disease prognosis and qualityof life, and in most cases their clinical course becomes independent ofgut disease activity.

IBD with skin EIMs is common, occurring in 2% to 34% of the IBDpopulation (Taverela V. F., Aliment Pharmacol Ther 2004; Suppl 4:50-53).Specifically, erythema nodosum and pyoderma gangrenosum are the mostcommon skin manifestations of IBD, while psoriasis is the activedermatological comorbidity disease observed most often, affecting 7%-11%of the IBD population (Danese S., et. al., Br J Dermatol, 1982; 106:323-330). IBD and these major skin EIMs in IBD share some commonpathogenic mechanisms including neutrophil and lymphocyte infiltration(Marzano A. V., et. al., Inflamm. Bowel Dis. 2014; 20:213-227). To thispoint, targeted immunosuppressive therapies have demonstrated efficacyin IBD with skin EIMs. For example, TNF-alpha inhibitors are known toreduce intestinal inflammation and induce clinical remission inindividuals with IBD, and are also known to reduce EIMs of IBD. However,a small percentage of individuals with IBD taking TNF-alpha inhibitorsexperience de novo paradoxical psoriasis (reporting a rate ranging from1.6 to 8.8%) despite beneficial intestinal effects while on treatment(Freling E., et. al., Am J Gastroenterol 2015; 110:1186-1196). Thepathophysiology of the paradoxical disease is not understood, but theleading hypothesis is that decreased TNF-alpha induces the activation ofautoreactive T cells and an increased interferon activity as well asother pro-inflammatory cytokines, such as IL-12, IL-17, IL-23. Recently,interferon-alpha (IFN-alpha) production by dermal plasmacytoid dendriticcells (DCs) has been identified as a key element in the early phase ofpsoriatic skin lesion induction. Plasmacytoid DCs, the natural IFN-alphaproducing cells, have recently been shown to infiltrate the skin ofindividuals with psoriasis and to produce IFN-alpha. IFN-alpha inducesthe expression of CXCR3 on T cells, facilitating homing to the skin(Nestle F. O., et. al., J Exp Med. 2005 Jul. 4; 202(1):135-43).

It is clear that existing treatments for IBD, and IBD skin EIMs,including TNF-alpha inhibitors, have limitations and a need remains fortherapies with sustained efficacy, improved safety, and convenientadministration (Paul C., et. al., J Eur Acad Dermatol Venereol 2012; 26(suppl 3): 1-10).

Spingosine-1-phosphate (S1P) is a spingolipid required by lymphocytes toexit the lymphoid tissue and enter the bloodstream via a chemotacticgradient. Agonists of the S1P receptor-1 (S1P1) block lymphocytemigration out of the lymph tissue through internalization of thereceptor, resulting in a sequestration of lymphocytes (Brinkmann V., et.al., J Biol Chem 2002; 277:21453-57). Recent clinical development ofS1P1 agonists and the resulting lymphocyte sequestration have potentialfor treating multiple autoimmune and chronic inflammatory diseasesincluding multiple sclerosis, IBD and psoriasis. Fingolimod was thefirst drug in this class to be approved the treatment of multiplesclerosis (Kappos L, et. al., N Engl J Med. 2010 Feb. 4;362(5):387-401). More recently the S1P1 receptor agonist ponesimod wasobserved to reduce the severity of chronic plaque psoriasis afterchronic oral administration in a phase 2 randomized clinical trial(Vaclavkova A., et. al., Lancet 2014; 384: 2036-45). In this study,ponesimod was associated with dyspnea, elevated liver enzymes,bradycardia, headache and dizziness. Furthermore, S1P1 agonists (FTY720,SEW2871) have been observed to have an anti-inflammatory impact on theproduction of IL-12 family cytokines, indicating therapeutic potentialfor S1P treatment of several inflammatory diseases like psoriasis(Schaper K., et. al., Mol Immunol. 2014 May; 59(1):10-8). Importantly, arecent report demonstrating S1P4 agonists inhibit plasmacytoid dendriticcell activation and interferon-alpha production suggest a potentialtherapeutic role for S1P1/S1P4 agonists like Compound 1 in paradoxicalpsoriasis (Dillmann C., et. al., J Immunol. 2016 Feb. 15;196(4):1579-90).

Pyoderma gangrenosum (PG) is considered to be a rare disorder associatedwith inflammation, mainly characterized by large skin ulcers (Cohen, P.R., Am J Clin Dermatol. 2009; 10(5):301-12; Marzano A. V., et. al.,Clinical and Experimental Immunology, 2010; 162: 1-11). The ulcers areknown to break down at a rapid rate and are painful, often turningnecrotic (Su W., et. al., J Cut. Path; 1986; 13: 323-330). Otherinflammatory diseases such as inflammatory bowel disorder (IBD),ulcerative colitis (UC) and Bechet's disease are indicated to share thesame clinicopathophysiology (Gameiro A, et. al., Clin. Cos. Inv.Dermatol; 2015; 8: 285-293). PG was considered to have a parallelrelationship with other underlying diseases (e.g., UC, IBD) with PGbeing the cutaneous manifestation (Brunsting L A, et. al. Arch DermatolSyph; 1930; 22:655-680), however this hypothesis was drawn into questionby Driesch (Von den Driesch P., Br. J. Dermatol; 1997; 137(6):1000-5)and published data suggesting consideration of PG as an independentdisease, irrespective of underlying disorders.

Based upon U.S. Department of Health and Human Services' NationalInstitutes of Health's Office of Rare Disease Research, the incidence ofPG has been estimated that each year in the United States, 1 person per100,000 people is affected (U.S. Department of Health & Human ServicesNational Institutes of Health,https://rarediseases.info.nih.gov/diseases/7510/pyoderma-gangrenosum).The incidence peak occurs between the ages of 20 to 50 years, with womenbeing more often affected than men (Wollina U., Orphanet Journal of RareDiseases; 2007, 2:19).

Diagnosis of PG is reliant on clinical signs, exclusion principle andsupported by histopathology of the biopsy (Wollina U., Orphanet Journalof Rare Diseases; 2007, 2:19; Weenig R. H., et. al., N Engl J Med; 2002;347:1412-1418). The histopathology can differ dependent on the timing(early stage-mild to moderate perivascular lymphocytic infiltrate;late-stage necrosis with dense lymphocytic infiltration along withinvolvement of blood vessels) and site of biopsy (Su W., et. al., J Cut.Path; 1986; 13: 323-330). The diagnosis using clinical signs alone hasbeen shown historically to lead to misdiagnoses as PG for at least 6categories including vascular occlusive or venous disease, vasculitis,cancer, infectious disease, exogenous tissue injury and drug reactions(Weenig R. H., et. al., N Engl J Med; 2002; 347:1412-1418), and supportof exclusion and histopathology is recommended for diagnosis.

The documented treatments for PG include, for example, systemiccorticosteroids and cyclosporin A. Combinations of steroids withcytotoxic drugs are used in resistant cases. The combination of steroidswith sulfa drugs or immunosuppressants has been used as steroid sparingmodalities. In some cases, anti-TNF therapy was reported to bebeneficial which suggests that inhibition of TNF may help.

Gevokizumab is a potent IL-1 beta monoclonal antibody with uniqueallosteric modulating properties and has the potential to treatindividuals with a wide variety of inflammatory and other diseases.Gevokizumab binds strongly to interleukin−1 beta (IL-1 beta), apro-inflammatory cytokine, and modulates the cellular signaling eventsthat produce inflammation. This agent was being developed as a potentialtreatment for PG; however, development was discontinued in 2016.

Agonists of the S1P1 receptor block lymphocyte migration out of thelymph tissue through internalization of the receptor, resulting in asequestration of lymphocytes (Brinkmann V., et. al., J Biol Chem; 2002;277:21453-57). Recent clinical development of S1P1 receptor agonists andthe resulting lymphocyte sequestration have potential for treatingmultiple autoimmune and chronic inflammatory diseases including multiplesclerosis, IBD and psoriasis. Fingolimod was the first drug in thisclass to be approved for the treatment of multiple sclerosis (Kappos L.,et. al., N Engl J Med.; 2010 Feb. 4; 362(5):387-401). More recently theS1P1 receptor agonist ponesimod was observed to reduce the severity ofchronic plaque psoriasis after chronic oral administration in a Phase 2randomized clinical trial (Vaclavkova A., et. al., Lancet; 2014; 384:2036-45). In this study, ponesimod was associated with dyspnea, elevatedliver enzymes, bradycardia, headache and dizziness. Furthermore, S1P1agonists (FTY720, SEW2871) have been observed to have ananti-inflammatory impact on the production of IL-12 family cytokines,indicating therapeutic potential for S1P treatment of severalinflammatory diseases like psoriasis (Schaper K., et. al., Mol Immunol.;2014 May; 59(1):10-8). Importantly, a recent report demonstrating S1P4agonists inhibition of plasmacytoid dendritic cell activation andinterferon-alpha production suggest a potential therapeutic role forS1P1/S1P4 agonists like Compound 1 in paradoxical psoriasis (DillmannC., et. al., Cells. J Immunol.; 2016 Feb. 15; 196(4):1579-90).

Histopathology of ulcerative pyoderma gangrenosum (PG) is characterizedby a dense dermal infiltrate composed mainly of neutrophils in biopsyfrom the central area of ulceration, and a mainly lymphocytic infiltratewith thrombosis of vessels and extravasated erythrocytes in biopsy fromthe border of the ulcer (Cohen, P. R., Am J Clin Dermatol.; 2009;10(5):301-12). In individuals with ulcerative PG the number ofT-lymphocytes are significantly higher at the wound edge compared to thewound bed. In contrast, neutrophils were significantly more numerous inthe wound bed than the wound edge (Marzano A. V., et. al., ExperimentalImmunology, 2010; 162: 1-11). This suggests that activated T-lymphocytesat the wound edge could promote ulcer formation. Further support forT-cell involvement in the disease comes from observations in individualswith PG that are characterized by an over-expression in the blood of theCD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts withrespect to healthy subjects (Quaglino P, et. al., J Eur Acad DermatolVenereol; 2016; 30: 655-8).

In addition to the potential anti-inflammatory benefits of systemiclymphocyte immunomodulation, S1P is known to exert anti-proliferativeeffects in human keratinocytes (Schuppel M., et. al., J Invest Dermatol2008; 128:1747-56), and inhibits dendritic cell migration (Reines I.,et. al., J Clin Invest Dermatol 2009; 129:1954-62). Thus, the potentialrole of S1P receptor modulation in skin EIMs of IBD might involve bothsystemic and local epidermal mechanisms.

Further, a differentiated profile for Compound 1 compared to other S1Pmodulators for the treatment of PG could arise from the hypothesis thatS1P4 as well as S1P1 receptor modulation could aid in neutrophiltrafficking (Allende M. L., J Biol Chem; 2011; 286: 7348-58).

Next generation S1P modulators, such as,(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, would offer a novel therapy for IBD individuals withskin EIMs.

Further, the evidence suggests that T-lymphocytes can play a role in PGand that reduction of lymphocytes by S1P1 receptor modulators representa novel therapeutic approach in PG. The availability of lymphocytetrafficking agents, such as,(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, would offer individuals a novel therapy for pyodermagangrenosum.

SUMMARY OF THE INVENTION

In its various embodiments, the present invention is directed to, interalia, methods of treating active skin extra-intestinal manifestations(EIM) in an individual with inflammatory bowel disease (IBD) in needthereof comprising administering a therapeutically effective amount of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In other embodiments, the present invention is directed to uses of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, in the manufacture of a medicament for the treatment ofactive skin extra-intestinal manifestations (EIM) in an individual withinflammatory bowel disease (IBD).

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: psoriasis, erythema nodosum (EN), andpyoderma gangrenosum (PG).

In some embodiments, the individual has psoriasis.

In some embodiments, the individual has erythema nodosum (EN).

In some embodiments, the individual has pyoderma gangrenosum (PG).

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: psoriasis, erythema nodosum (EN), andpyoderma gangrenosum (PG).

In some embodiments, the skin extra-intestinal manifestations (EIM) ispsoriasis.

In some embodiments, the skin extra-intestinal manifestations (EIM) iserythema nodosum (EN).

In some embodiments, the skin extra-intestinal manifestations (EIM) ispyoderma gangrenosum (PG).

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg to about 5 mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 2mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is selected from: Compound 1, acalcium salt of Compound 1, and an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of the L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is a crystalline free-plate habit ofthe non-solvated L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered orally.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is formulated as a capsule or tabletsuitable for oral administration.

In some embodiments, the methods further comprise administering Compound1, or a pharmaceutically salt, solvate, or hydrate thereof, incombination with a therapeutically effective amount of a compoundselected from the group consisting of: a corticosteroid, a5-aminosalicylic acid derivative, and a TNF-alpha inhibitor.

In some embodiments, the corticosteroid is cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone, and fludrocortisone.

In some embodiments, the 5-aminosalicylic acid derivative is selectedfrom the group consisting ot: balsalazide, mesalamine, olsalazine, andsulfasalazine.

In some embodiments, the TNF-alpha inhibitor is selected from the groupconsisting of: as infliximab (Remicade®), adalimumab (Humira®),certolizumab pegol (Cimzia®), and golimumab (Simponi®), and etanercept(Enbrel®).

In further embodiments, the present invention is directed to, interalia, methods of treating pyoderma gangrenosum (PG) in an individual inneed thereof comprising administering a therapeutically effective amountof(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In other embodiments, the present invention is directed to uses of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, in the manufacture of a medicament for the treatment ofpyoderma gangrenosum (PG).

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: an inflammatory bowel disease, arthritis,a hematological disease, and an autoinflammatory disease.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: ulcerative colitis and Crohn's disease.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: rheumatoid arthritis and seronegativearthritis.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: myelocytic leukemia, hairy cell leukemia,myelofibrosis, myeloid metaplasia, and monoclonal gammopathy.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: PAPA syndrome and granulomatosis withpolyangiitis.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg to about 5 mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 2mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is selected from: Compound 1, acalcium salt of Compound 1, and an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of the L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is a crystalline free-plate habit ofthe non-solvated L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered orally.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is formulated as a capsule or tabletsuitable for oral administration.

In some embodiments, the methods further comprise administering Compound1, or a pharmaceutically salt, solvate, or hydrate thereof, incombination with a therapeutically effective amount of a compoundselected from the group consisting of: a corticosteroid, animmunosuppressant, a biologic, an anti-inflammatory agent, and anantibiotic.

In some embodiments, the corticosteroid is cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone, and fludrocortisone.

In some embodiments, the immunosuppressant is selected from the groupconsisting of: cyclosporin A, tacrolimus, and mycophenolic acid.

In some embodiments, the immunosuppressant is cyclosporin A.

In some embodiments, the biologic is selected from the group consistingof: abatacept, adalimumab, adalimumab-atto, anakinra, certolizumabpegol, etanercept, etanercept-szzs, golimumab, infliximab,infliximab-dyyb, rituximab, tocilizumab, tofacitinib, vedolizumab, andnatalizumab.

In some embodiments, the anti-inflammatory agent is selected from thegroup consisting of: aceclofenac, vedolizumab, aspirin, celecoxib,clonixin, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam,enolic acid, etodolac, etoricoxib, fenoprofen, flufenamic acid,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,licofelone, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid,meloxicam, nabumetone, naproxen, oxaprozin, parecoxib, phenylbutazone,piroxicam, salicylic acid, salsalate, sulindac, tenoxicam, tolfenamicacid, and tolmetin.

In some embodiments, the antibiotic is selected from the groupconsisting of: ceftobiprole, ceftaroline, clindamycin, dalbavancin,daptomycin, fusidic acid, linezolid, mupirocin, oritavancin, tedizolid,telavancin, tigecycline, vancomycin, amikacin, gentamicin, kanamycin,neomycin, netilmicin, tobramycin, and paromomycin.

In some embodiments, the antibiotic is selected from the groupconsisting of: mupirocin and gentamicin.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a clinical protocol for the treatment of IBD with skin EIMswith Compound 1.

FIG. 2 shows a clinical protocol for the treatment of pyodermagangrenosum (PG) with Compound 1.

FIG. 3 shows a PXRD Pattern overlay for the L-arginine salt of Compound1 showing the peak intensity differences between plates and spherulitesindicating a higher degree of crystallinity for the plates compared tothe spherulites. Also shown is the lower sample-related backgroundscatter (i.e., a lower amorphous halo contribution) for the plates.However, the plates and spherulites are observed to show the samecrystal phase.

FIG. 4 shows a flowchart for the preparation of core tablets of theL-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1).

DETAILED DESCRIPTION OF THE INVENTION

In its various embodiments, the present invention is directed to, interalia, methods of treating active skin extra-intestinal manifestations(EIM) in an inflammatory bowel disease (IBD) individual in need thereofcomprising administering a therapeutically effective amount of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In other embodiments, the present invention is directed to uses of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, in the manufacture of a medicament for the treatment ofextra-intestinal manifestations (EIM) in an individual with inflammatorybowel disease (IBD).

In other embodiments, the present invention is directed to(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, for use in the treatment of extra-intestinalmanifestations (EIM) in an individual with inflammatory bowel disease(IBD).

In some embodiments, the EIM is a dermal EIM. In some embodiments, theEIM is an active skin EIM.

The present invention further provides, inter alia, methods of treatingpyoderma gangrenosum (PG) in an individual in need thereof comprisingadministering a therapeutically effective amount of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), of a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In other embodiments, the present invention is directed to uses of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, in the manufacture of a medicament for the treatment ofpyoderma gangrenosum (PG) in an individual.

In other embodiments, the present invention is directed to(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, for use in the treatment of pyoderma gangrenosum.

Certain processes for the preparation of Compound 1 and the L-argininesalt of Compound 1 have been previously described; see WO2010/011316 andWO2011/094008. In addition, the novel crystalline plate habit for theL-arginine salt of Compound 1 has been previously described and isreferred to herein as, “crystalline free-plate habit of the non-solvatedL-arginine salt of Compound 1”; see WO2016/209809.

The following is a list of abbreviations: ACS (acute coronary syndrome);ADL (activities of daily living); AE (adverse event); ALB (albumin);ALK-P (alkaline phosphatase); ALT (alanine aminotransferase (SGPT)); AST(aspartate aminotransferase (SGOT)); bpm (beats per minute); BUN (bloodurea nitrogen); Ca (calcium); CBC (complete blood count); CFR (Code ofFederal Regulations); CI (confidence interval); CIA (collagen-inducedarthritis); Cl (chloride); CL/F (apparent oral clearance); CMO (contractmanufacturing organization); CRF (case report form); CRF (case reportform); CRO (contract research organization); CRP (C-reactive protein); D(day); DLQI (Dermatology Life Quality Index); EAE (experimentalautoimmune encephalomyelitis); ECG (electrocardiogram); ED50 (medianeffective dose); EIM (extra-intestinal manifestation); ELISA(enzyme-linked immunosorbent assay); EOS (end of study); EOT (end oftreatment); FDA (Food and Drug Administration); FEF25-75% (mean forcedexpiratory flow between 25 and to 75% of FVC); FEV1 (forced expiratoryvolume in the first second); FU (follow-up); FVC (forced vitalcapacity); GCP (Good Clinical Practice); GGT (gamma glutamyltransferase); h (hour); Hb (hemoglobin); HBsAg (hepatitis B surfaceantigen); hCG (human chorionic gonadotropin); Hct (hematocrit); HCV(hepatitis C virus); HDPE (High-density polyethylene); HIV (humanimmunodeficiency virus); HR (heart rate); HREC (human resource ethicscommittee (AUS)); IBD (Inflammatory Bowel Disease); IBDQ (InflammatoryBowel Disease Questionnaire); IBDQ (Inflammatory Bowel DiseaseQuestionnaire); ICF (informed consent form); ICH (InternationalConference on Harmonization); IEC (Independent Ethics Committee); IND(Investigational New Drug); INR (international normalized ratio); IRB(Institutional Review Board); IUD (intrauterine device); IUS(hormone-releasing system); kg (kilogram); LDH (lactate dehydrogenase);MCH (mean corpuscular hemoglobin); MCV (mean corpuscular volume); MedDRA(Medical Dictionary for Regulatory Activities); mg (milligram); MI(myocardial infarction); mL (milliliter); mm (millimeter); mmHg(millimeters of mercury); MRSD (maximum recommended starting dose); Na(sodium); NOAEL (no observed adverse effect level); OCT (opticalcoherence tomography); OTC (over-the-counter); PA (Posteroanterior);PASI (Psoriasis Area and Severity Index); PBL (peripheral bloodlymphocyte); PFT (pulmonary function test); PG (pyoderma gangrenosum);PGA (Physicians Global Assessments); PI (Principal Investigator); PPD (ACRO responsible for SAE processing in this study); PPD PVG (APharmacovigilance department of PPD); PRO (patient reported outcome);PRO (patient reported outcome); PT (prothrombin time); PTT (partialthromboplastin time); PV (pharmacovigilance); q.d. (quaque die (oncedaily)); RBC (red blood cell (count)); RT-PCR (real-time polymerasechain reaction); S1P (sphingosine 1-phosphate receptor); S1P(1-5)(sphingosine 1-phosphate (1-5) receptor); SAE (serious adverse event);SAP (statistical analysis plan); SBP (systolic blood pressure); SD(standard deviation); sec (second); SOP(s) (standard operatingprocedure(s)); t_(1/2) (elimination half-life); TEM (T effector memorycells); TIA (Transient Ischemic Attack); TIA (transient ischemicattack); tmax (the median time to reach maximum plasma concentration);UC (ulcerative colitis); ULN (upper limit of normal); VAS (visualanalogue scale); VS (vital signs); VZV (varicella zoster virus); WBC(white blood cell); WHO (World Health Organization); and WHODRUG (WorldHealth Organization Drug Dictionary).

Crystalline L-Arginine Salt of Compound 1

The crystalline free-plate habit or morphology and processes useful inthe preparation of a crystalline free-plate habit of L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)-benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid are described in WO2016/209809. The plates were discovered from thenovel synthetic methods and were shown to be thin hexagonal-like plateswith two opposite sides of the plate being longer that the other sides(i.e., elongated hexagonal plate). However, due to the thincharacteristic of the plates, a complete unbroken plate is rarely seen.Instead, what is generally observed are large to small broken pieces ofthe thin hexagonal-like plates. It is understood by those skilled in theart that microscopy is one of the more useful techniques to distinguishtwo crystalline habits or morphologies. This is particularly useful when2 or more morphologies are associated with the same or substantially thesame crystal phase as is the case with the L-arginine salt ofCompound 1. Comparing the PXRD patterns of the habit prepared previously(i.e., WO2011/094008 and Example 2 infra) and the plate habit preparedas described in WO2016/209809 (i.e., see FIG. 3 , PXRD overlay betweenspherulites and plates) it was observed that the two PXRD patterns werethe same or substantially the same, thus the two habits represented thesame crystal phase.

Although the two habits revealed the same or substantially the same PXRDpattern, a higher degree of crystallinity was observed for the platehabit as indicated by substantially higher peak intensities and yetlower sample-related background scatter (i.e., a lower amorphous halocontribution). Since sample size and sample preparation can affect peakintensities and sample-related background scatter, and since the twohabits share the same crystal phase, PXRD may not be considered the mostappropriate test method to distinguish between two habits. However, PXRDdoes allow for determining whether two habits have the same crystalphase or different crystal phases. For determining different habits,microscopy is one of the more useful methods. Accordingly, the skilledperson would be capable of reviewing a micrograph for a crystal habitand readily determine the crystal habit.

In addition to the techniques recognized in the art, specific surfacecan also be used to characterize a habit, such as the free-plates.Accordingly, the specific surface area values disclosed in the presentinvention have been obtained by means of a specific surface areaanalysis technique based on the BET (Brunauer, Emmett and Teller)theory, which is a well-accepted theory known in the art for thecalculation of surface areas of solids by means of measuring theirphysical adsorption of gas molecules (see: Brunauer, S.; Emmett, P. H.;and Teller, E.; J. Am. Chem. Soc., 1938, 60, 309). In particular, thespecific surface area values measured in the present invention have beencalculated from the BET surface area plot obtained by measuring thequantity of nitrogen gas molecules adsorbed by a weighted amount ofsolid at different relative pressures (P/P₀) within the range 0.05-0.3(P/P₀), at 77.3 K. The measurement of the adsorption of gas moleculeswas carried out by means of a Micromeritics™ TriStar II BET surfaceanalyzer having the characteristics as set out below in Example 4.Namely, nitrogen gas was used for the adsorption measurement. The samplefor each analysis was degassed at 25° C. for 960 minutes under vacuum(i.e., 100 mm/Hg). The determination of the adsorption of nitrogen wasmeasured at 77.3 K at eleven relative pressures (P/P₀) sufficientlydispersed within the range of about 0.05 to about 0.30 (i.e. elevenabsolute pressures in the range of about 36 mm Hg to about 223 mm Hgrelative to the saturated pressure at the time of measurement thatranged from about 738 mmHg to about 743 mmHg).

One aspect of the present invention relates to a novel crystalline platemorphology of L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)aceticacid as described herein.

One aspect of the present invention relates to a crystalline free-platehabit of L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid.

In some embodiments, the crystalline free-plate habit has a powder X-raydiffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°,16.4°±0.2°, and 20.5°±0.2θ. In some embodiments, the crystallinefree-plate habit has a powder X-ray diffraction pattern comprisingpeaks, in terms of 2θ, at 8.2°±0.2°, 20.5°±0.2°, and 24.6°±0.2°. In someembodiments, the crystalline free-plate habit has a powder X-raydiffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°,16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°. In some embodiments, thecrystalline free-plate habit has a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°,24.6°±0.2°, and 28.8°±0.2°. In some embodiments, the crystallinefree-plate habit has a powder X-ray diffraction pattern comprisingpeaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°,28.8°±0.2°, and 37.3°±0.2θ.

In some embodiments, the crystalline free-plate habit has a differentialscanning calorimetry trace comprising an endotherm with an extrapolatedonset temperature of 205.0° C. to 208.5° C. at a scan rate of 10°C./minute. In some embodiments, the crystalline free-plate habit has adifferential scanning calorimetry trace comprising an endotherm with anextrapolated onset temperature of 205.0° C. to 208.1° C. at a scan rateof 10° C./minute. In some embodiments, the crystalline free-plate habithas a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.5° C. to 208.5° C. at ascan rate of 10° C./minute. In some embodiments, the crystallinefree-plate habit has a differential scanning calorimetry tracecomprising an endotherm with an extrapolated onset temperature of 206.0°C. to 208.5° C. at a scan rate of 10° C./minute. In some embodiments,the crystalline free-plate habit has a differential scanning calorimetrytrace comprising an endotherm with an extrapolated onset temperature of206.5° C. to 208.5° C. at a scan rate of 10° C./minute. In someembodiments, the crystalline free-plate habit has a differentialscanning calorimetry trace comprising an endotherm with an extrapolatedonset temperature of 205.5° C. to 208.1° C. at a scan rate of 10°C./minute. In some embodiments, the crystalline free-plate habit has adifferential scanning calorimetry trace comprising an endotherm with anextrapolated onset temperature of 206.5° C. to 208.1° C. at a scan rateof 10° C./minute.

In some embodiments, the crystalline free-plate habit has a differentialscanning calorimetry trace comprising an endotherm with an extrapolatedonset temperature of 207.0° C. to 208.1° C. at a scan rate of 10°C./minute.

In some embodiments, the crystalline free-plate habit has a dynamicmoisture sorption (DMS) profile with an adsorption phase from 30% RH to90% RH wherein the crystalline free-plate habit gains about 0.3% weightor less at 90% RH. In some embodiments, the crystalline free-plate habithas a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.2% weight or less at 90% RH.

One aspect of the present invention relates to a crystalline free-platehabit of L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid having a BET specific surface area of about 0.05 m²/g, about 0.1m²/g, about 0.15 m²/g, about 0.2 m²/g, about 0.25 m²/g, about 0.3 m²/g,about 0.35 m²/g, about 0.4 m²/g, about 0.45 m²/g, about 0.5 m²/g, about0.55 m²/g, about 0.6 m²/g, about 0.65 m²/g, or about 0.7 m²/g to about2.0 m²/g, about 2.5 m²/g, about 3.0 m²/g, about 3.5 m²/g, about 4.0m²/g, about 4.5 m²/g, about 5.0 m²/g, about 5.5 m²/g, about 6.0 m²/g,about 6.5 m²/g, about 7.0 m²/g, about 7.5 m²/g, about 8.0 m²/g, about8.5 m²/g, about 9.0 m²/g, or about 9.5 m²/g.

In some embodiments, the crystalline free-plate habit has a BET specificsurface area of about 0.1 m²/g to about 5.0 m²/g. In some embodiments,the crystalline free-plate habit has a BET specific surface area ofabout 0.1 m²/g to about 4.0 m²/g. In some embodiments, the crystallinefree-plate habit has a BET specific surface area of about 0.3 m²/g toabout 4.0 m²/g. In some embodiments, the crystalline free-plate habithas a BET specific surface area of about 0.5 m²/g to about 4.0 m²/g. Insome embodiments, the crystalline free-plate habit has a BET specificsurface area of about 0.6 m²/g to about 4.0 m²/g. In some embodiments,the crystalline free-plate habit has a BET specific surface area ofabout 0.3 m²/g to about 3.0 m²/g. In some embodiments, the crystallinefree-plate habit has a BET specific surface area of about 0.4 m²/g toabout 2.0 m²/g. In some embodiments, the crystalline free-plate habithas a BET specific surface area of about 0.5 m²/g to about 1.8 m²/g. Insome embodiments, the crystalline free-plate habit has a BET specificsurface area of about 0.6 m²/g to about 1.6 m²/g.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, 20.50±0.2°, 24.6°±0.2°, 28.8°±0.2°, and37.3°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.0° C. to 208.5° C. at ascan rate of 10° C./minute; and/or

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 206.5° C. to t 208.5° C. at ascan rate of 10° C./minute; and/or

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 20.5°±0.2°, and 24.6°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.5° C. to 208.5° C. at ascan rate of 10° C./minute; and/or

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.2% weight or less at 90% RH.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, and 20.5°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 207.1° C. to 208.1° C. at ascan rate of 10° C./minute; and/or

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.2% weight or less at 90% RH.

In some embodiments, the crystalline free-plate habit has:

1) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.0° C. to 208.5° C. at ascan rate of 10° C./minute; and/or

2) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH.

In some embodiments, the crystalline free-plate habit has:

1) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 206.5° C. to t 208.5° C. at ascan rate of 10° C./minute; and/or

2) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH.

In some embodiments, the crystalline free-plate habit has:

1) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.5° C. to 208.5° C. at ascan rate of 10° C./minute; and/or

2) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.2% weight or less at 90% RH.

In some embodiments, the crystalline free-plate habit has:

1) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 207.1° C. to 208.1° C. at ascan rate of 10° C./minute; and/or

2) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein the crystalline free-plate habit gainsabout 0.2% weight or less at 90% RH. In some embodiments, thecrystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, and 20.5°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature. of 205.0° C. to 208.5° C. at ascan rate of 10° C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein said crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH; and/or

4) a BET specific surface area of about 0.1 m²/g to about 5.0 m²/g. Insome embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 20.5°±0.2°, and 24.6°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.5° C. to t 208.5° C. at ascan rate of 10° C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein said crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH; and/or

4) a BET specific surface area of about 0.1 m²/g to about 4.0 m²/g.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 20.5°±0.2°, and 24.6°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.5° C. to t 208.5° C. at ascan rate of 10° C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein said crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH; and/or

4) a BET specific surface area of about 0.3 m²/g to about 3.0 m²/g.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.5° C. to 208.5° C. at ascan rate of 10° C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein said crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH; and/or

4) a BET specific surface area of about 0.6 m²/g to about 4.0 m²/g.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2°,at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 206.5° C. to t 208.5° C. at ascan rate of 10° C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein said crystalline free-plate habit gainsabout 0.3% weight or less at 90% RH; and/or

4) a BET specific surface area of about 0.4 m²/g to about 2.0 m²/g.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°, and 28.8°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 206.5° C. to 208.1° C. at ascan rate of 10° C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein said crystalline free-plate habit gainsabout 0.2% weight or less at 90% RH; and/or

4) a BET specific surface area of about 0.5 m²/g to about 1.8 m²/g.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°, 28.8°±0.2°, and37.3°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 205.5° C. to 208.1° C. at ascan rate of 10° C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein said crystalline free-plate habit gainsabout 0.2% weight or less at 90% RH; and/or

4) a BET specific surface area of about 0.6 m²/g to about 4.0 m²/g.

In some embodiments, the crystalline free-plate habit has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°, 28.8°±0.2°, and37.3°±0.2°;

2) a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 207.1° C. to 208.1° C. at ascan rate of 10° C./minute;

3) a dynamic moisture sorption (DMS) profile with an adsorption phasefrom 30% RH to 90% RH wherein said crystalline free-plate habit gainsabout 0.2% weight or less at 90% RH; and/or

4) a BET specific surface area of about 0.6 m²/g to about 1.6 m²/g.

One aspect of the present invention relates to a crystalline free-platehabit of L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid having a powder X-ray diffraction pattern comprising peaks, interms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, and 20.5°±0.2°. In someembodiments, the crystalline free-plate habit has a powder X-raydiffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°,20.5°±0.2°, and 24.6°±0.2°. In some embodiments, the crystallinefree-plate habit has a powder X-ray diffraction pattern comprisingpeaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, and24.6°±0.2°. In some embodiments, the crystalline free-plate habit has apowder X-ray diffraction pattern comprising peaks, in terms of 2θ, at8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°, and 28.8°±0.2°. In someembodiments, the crystalline free-plate habit has a powder X-raydiffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°,16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°, 28.8°±0.2°, and 37.3°±0.2°.

One aspect of the present invention relates to a crystalline free-platehabit of L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid having a differential scanning calorimetry trace comprising anendotherm with an extrapolated onset temperature of 205.0° C. to 208.5°C. when scanned at 10° C. per minute. In some embodiments, thecrystalline free-plate habit has a differential scanning calorimetrytrace comprising an endotherm with an extrapolated onset temperature of205.0° C. to 208.1° C. at a scan rate of 10° C./minute. In someembodiments, the crystalline free-plate habit has a differentialscanning calorimetry trace comprising an endotherm with an extrapolatedonset temperature of 205.5° C. to 208.5° C. at a scan rate of 10°C./minute. In some embodiments, the crystalline free-plate habit has adifferential scanning calorimetry trace comprising an endotherm with anextrapolated onset temperature of 205.5° C. to 208.1° C. at a scan rateof 10° C./minute. In some embodiments, the crystalline free-plate habithas a differential scanning calorimetry trace comprising an endothermwith an extrapolated onset temperature of 206.0° C. to 208.5° C. at ascan rate of 10° C./minute. In some embodiments, the crystallinefree-plate habit has a differential scanning calorimetry tracecomprising an endotherm with an extrapolated onset temperature of 206.5°C. to 208.5° C. at a scan rate of 10° C./minute. In some embodiments,the crystalline free-plate habit has a differential scanning calorimetrytrace comprising an endotherm with an extrapolated onset temperature of206.5° C. to 208.1° C. at a scan rate of 10° C./minute. In someembodiments, the crystalline free-plate habit has a differentialscanning calorimetry trace comprising an endotherm with an extrapolatedonset temperature of 207.0° C. to 208.1° C. at a scan rate of 10°C./minute. In some embodiments, the crystalline free-plate habit has apowder X-ray diffraction pattern comprising peaks, in terms of 2θ, at8.2°±0.2°, 16.4°±0.2°, and 20.5°±0.2°. In some embodiments, thecrystalline free-plate habit has a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 8.2°±0.2°, 20.5°±0.2°, and24.6°±0.2°. In some embodiments, the crystalline free-plate habit has apowder X-ray diffraction pattern comprising peaks, in terms of 2θ, at8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°. In some embodiments,the crystalline free-plate habit has a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°,24.6°±0.2°, and 28.8°±0.2°. In some embodiments, the crystallinefree-plate habit has a powder X-ray diffraction pattern comprisingpeaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°,28.8°±0.2°, and 37.3°±0.2°.

One aspect of the present invention relates to a crystalline free-platehabit of L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid having a dynamic moisture sorption (DMS) profile with an adsorptionphase from 30% RH to 90% RH wherein the crystalline free-plate habitgains about 0.3% weight or less at 90% RH. In some embodiments, thecrystalline free-plate habit has a dynamic moisture sorption (DMS)profile with an adsorption phase from 30% RH to 90% RH wherein thecrystalline free-plate habit gains about 0.2% weight or less at 90% RH.In some embodiments, the crystalline free-plate habit has a powder X-raydiffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°,16.4°±0.2°, and 20.5°±0.2°. In some embodiments, the crystallinefree-plate habit has a powder X-ray diffraction pattern comprisingpeaks, in terms of 2θ, at 8.2°±0.2°, 20.5°±0.2°, and 24.6°±0.2°. In someembodiments, the crystalline free-plate habit has a powder X-raydiffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°,16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°. In some embodiments, thecrystalline free-plate habit has a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°,24.6°±0.2°, and 28.8°±0.2°. In some embodiments, the crystalline freeplate habit has a powder X-ray diffraction pattern comprising peaks, interms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°,28.8°±0.2°, and 37.3°±0.2°.

One aspect of the present invention relates to a crystalline free-platehabit of L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid having a BET specific surface area of about 0.1 m²/g to about 5.0m²/g. In some embodiments, the crystalline free-plate habit has a BETspecific surface area of about 0.1 m²/g to about 4.0 m²/g. In someembodiments, the crystalline free-plate habit has a BET specific surfacearea of about 0.3 m²/g to about 4.0 m²/g. In some embodiments, thecrystalline free-plate habit has a BET specific surface area of about0.5 m²/g to about 4.0 m²/g. In some embodiments, the crystallinefree-plate habit has a BET specific surface area of about 0.6 m²/g toabout 4.0 m²/g. In some embodiments, the crystalline free-plate habithas a BET specific surface area of about 0.3 m²/g to about 3.0 m²/g. Insome embodiments, the crystalline free-plate habit has a BET specificsurface area of about 0.4 m²/g to about 2.0 m²/g. In some embodiments,the crystalline free-plate habit has a BET specific surface area ofabout 0.5 m²/g to about 1.8 m²/g. In some embodiments, the crystallinefree-plate habit has a BET specific surface area of about 0.6 m²/g toabout 1.6 m²/g. In some embodiments, the crystalline free-plate habithas a powder X-ray diffraction pattern comprising peaks, in terms of 2θ,at 8.2°±0.2°, 16.4°±0.2°, and 20.5°±0.2°. In some embodiments, thecrystalline free-plate habit has a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 8.2°±0.2°, 20.5°±0.2°, and24.6°±0.2°. In some embodiments, the crystalline free-plate habit has apowder X-ray diffraction pattern comprising peaks, in terms of 2θ, at8.2°±0.2°, 16.4°+0.2°, 20.5°±0.2°, and 24.6°±0.2°. In some embodiments,the crystalline free-plate habit has a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°,24.6°±0.2°, and 28.8°±0.2°. In some embodiments, the crystallinefree-plate habit has a powder X-ray diffraction pattern comprisingpeaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°,28.8°±0.2°, and 37.3°±0.2°.

Certain Embodiments

In its various embodiments, the present invention is directed to, interalia, methods of treating active skin extra-intestinal manifestations(EIM) in an inflammatory bowel disease (IBD) individual in need thereofcomprising administering a therapeutically effective amount of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In other embodiments, the present invention is directed to uses of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, in the manufacture of a medicament for the treatment ofactive skin extra-intestinal manifestations (EIM) in an individual withinflammatory bowel disease (IBD).

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: psoriasis, erythema nodosum (EN), andpyoderma gangrenosum (PG).

In some embodiments, the individual has psoriasis.

In some embodiments, the individual has erythema nodosum (EN).

In some embodiments, the individual has pyoderma gangrenosum (PG).

In some embodiments, the skin extra-intestinal manifestations (EIM) ispsoriasis.

In some embodiments, the skin extra-intestinal manifestations (EIM) iserythema nodosum (EN).

In some embodiments, the skin extra-intestinal manifestations (EIM) ispyoderma gangrenosum (PG).

In some embodiments, the skin extra-intestinal manifestations (EIM) ispyoderma gangrenosum (PG).

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg to about 5 mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg to about 2 mg.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg or about 2 mg.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 2mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is selected from: Compound 1, acalcium salt of Compound 1, and an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of the L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is a crystalline free-plate habit ofthe non-solvated L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered orally.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is formulated as a capsule or tabletsuitable for oral administration.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered once daily.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered without food.

In some embodiments, the methods further comprise administering Compound1, or a pharmaceutically salt, solvate, or hydrate thereof, incombination with a therapeutically effective amount of a compoundselected from the group consisting of: a corticosteroid, a5-aminosalicylic acid derivative, and a TNF-alpha inhibitor.

In some embodiments, Compound 1 or a pharmaceutically salt, solvate, orhydrate thereof is administered to an individual who is also beingadministered a therapeutically effective amount of a compound selectedfrom the group consisting of: a corticosteroid, a 5-aminosalicylic acidderivative, and a TNF-alpha inhibitor.

In some embodiments, when administered with Compound 1, an individual isadministered a reduced amount of the compound selected from the groupconsisting of: a corticosteroid, a 5-aminosalicylic acid derivative, anda TNF-alpha inhibitor.

In some embodiments, the corticosteroid is cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone, and fludrocortisone.

In some embodiments, the 5-aminosalicylic acid derivative is selectedfrom the group consisting of: balsalazide, mesalamine, olsalazine, andsulfasalazine.

In some embodiments, the TNF-alpha inhibitor is selected from the groupconsisting of: as infliximab (Remicade®), adalimumab (Humira®),certolizumab pegol (Cimzia®), and golimumab (Simponi®), and etanercept(Enbrel®).

In still other embodiments, the present invention is directed to, interalia, methods of treating pyoderma gangrenosum (PG) in an individual inneed thereof comprising administering a therapeutically effective amountof(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: an inflammatory bowel disease, arthritis,a hematological disease, and an autoinflammatory disease.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: ulcerative colitis and Crohn's disease.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: rheumatoid arthritis and seronegativearthritis.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: myelocytic leukemia, hairy cell leukemia,myelofibrosis, myeloid metaplasia, and monoclonal gammopathy.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: PAPA syndrome and granulomatosis withpolyangiitis.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg to about 5 mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg to about 2 mg.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg or about 2 mg.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 2mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is selected from: Compound 1, acalcium salt of Compound 1, and an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of the L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is a crystalline free-plate habit ofthe non-solvated L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered orally.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is formulated as a capsule or tabletsuitable for oral administration.

In some embodiments, the methods further comprise administering Compound1, or a pharmaceutically salt, solvate, or hydrate thereof, incombination with a therapeutically effective amount of a compoundselected from the group consisting of: a corticosteroid, animmunosuppressant, a biologic, an anti-inflammatory agent, and anantibiotic.

In some embodiments, the corticosteroid is cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone, and fludrocortisone.

In some embodiments, the immunosuppressant is selected from the groupconsisting of: cyclosporin A, tacrolimus, and mycophenolic acid.

In some embodiments, the immunosuppressant is cyclosporin A.

In some embodiments, the biologic is selected from the group consistingof: abatacept, adalimumab, adalimumab-atto, anakinra, certolizumabpegol, etanercept, etanercept-szzs, golimumab, infliximab,infliximab-dyyb, rituximab, tocilizumab, tofacitinib, vedolizumab, andnatalizumab.

Additional names, such as their marketed names for the biologicsinclude: abatacept (Orencia®), adalimumab (Humira®), adalimumab-atto(Amjevita®) a biosimilar to Humira, anakinra (Kineret®), certolizumabpegol (Cimzia®), etanercept (Enbrel®, etanercept-szzs (Erelzi®) abiosimilar to Enbrel, golimumab (Simponi®, Simponi Aria®), infliximab(Remicade®), infliximab-dyyb (Inflectra®) a biosimilar to Remicade,rituximab (Rituxan®), tocilizumab (Actemra®), tofacitinib (Xeljanz®),vedolizumab (Entyvio®), and natalizumab (Tysabri®).

In some embodiments, the anti-inflammatory agent is selected from thegroup consisting of: aceclofenac, vedolizumab, aspirin, celecoxib,clonixin, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam,enolic acid, etodolac, etoricoxib, fenoprofen, flufenamic acid,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,licofelone, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid,meloxicam, nabumetone, naproxen, oxaprozin, parecoxib, phenylbutazone,piroxicam, salicylic acid, salsalate, sulindac, tenoxicam, tolfenamicacid, and tolmetin.

In some embodiments, the antibiotic is selected from the groupconsisting of: ceftobiprole, ceftaroline, clindamycin, dalbavancin,daptomycin, fusidic acid, linezolid, mupirocin, oritavancin, tedizolid,telavancin, tigecycline, vancomycin, amikacin, gentamicin, kanamycin,neomycin, netilmicin, tobramycin, and paromomycin.

In some embodiments, the antibiotic is selected from the groupconsisting of: mupirocin and gentamicin.

In other embodiments, the present invention is directed to uses of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, in the manufacture of a medicament for the treatment ofpyoderma gangrenosum (PG) in an individual.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: an inflammatory bowel disease, arthritis,a hematological disease, and an autoinflammatory disease.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: ulcerative colitis and Crohn's disease.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: rheumatoid arthritis and seronegativearthritis.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: myelocytic leukemia, hairy cell leukemia,myelofibrosis, myeloid metaplasia, and monoclonal gammopathy.

In some embodiments, the individual has at least one condition selectedfrom the group consisting of: PAPA syndrome and granulomatosis withpolyangiitis.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 1mg to about 5 mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is in an amount equivalent to about 2mg of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is selected from: Compound 1, acalcium salt of Compound 1, and an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of the L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is a crystalline free-plate habit ofthe non-solvated L-arginine salt of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is an anhydrous, non-solvatedcrystalline form of Compound 1.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered orally.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is formulated as a capsule or tabletsuitable for oral administration.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered once daily.

In some embodiments, the Compound 1, or a pharmaceutically acceptablesalt, hydrate, or solvate thereof, is administered without food.

In some embodiments, the methods further comprise administering Compound1, or a pharmaceutically salt, solvate, or hydrate thereof, incombination with a therapeutically effective amount of a compoundselected from the group consisting of: a corticosteroid, animmunosuppressant, a biologic, an anti-inflammatory agent, and anantibiotic.

In some embodiments, the corticosteroid is cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone, and fludrocortisone.

In some embodiments, the immunosuppressant is selected from the groupconsisting of: cyclosporin A, tacrolimus, and mycophenolic acid.

In some embodiments, the immunosuppressant is cyclosporin A.

In some embodiments, the biologic is selected from the group consistingof: abatacept, adalimumab, adalimumab-atto, anakinra, certolizumabpegol, etanercept, etanercept-szzs, golimumab, infliximab,infliximab-dyyb, rituximab, tocilizumab, tofacitinib, vedolizumab, andnatalizumab.

Additional names, such as their marketed names for the biologicsinclude: abatacept (Orencia®), adalimumab (Humira®), adalimumab-atto(Amjevita®) a biosimilar to Humira, anakinra (Kineret®), certolizumabpegol (Cimzia®), etanercept (Enbrel®, etanercept-szzs (Erelzi®) abiosimilar to Enbrel, golimumab (Simponi®, Simponi Aria®), infliximab(Remicade®), infliximab-dyyb (Inflectra®) a biosimilar to Remicade,rituximab (Rituxan®), tocilizumab (Actemra®), tofacitinib (Xeljanz®),vedolizumab (Entyvio®), and natalizumab (Tysabri®).

In some embodiments, the anti-inflammatory agent is selected from thegroup consisting of: aceclofenac, vedolizumab, aspirin, celecoxib,clonixin, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam,enolic acid, etodolac, etoricoxib, fenoprofen, flufenamic acid,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,licofelone, lornoxicam, loxoprofen, meclofenamic acid, mefenamic acid,meloxicam, nabumetone, naproxen, oxaprozin, parecoxib, phenylbutazone,piroxicam, salicylic acid, salsalate, sulindac, tenoxicam, tolfenamicacid, and tolmetin.

In some embodiments, the antibiotic is selected from the groupconsisting of: ceftobiprole, ceftaroline, clindamycin, dalbavancin,daptomycin, fusidic acid, linezolid, mupirocin, oritavancin, tedizolid,telavancin, tigecycline, vancomycin, amikacin, gentamicin, kanamycin,neomycin, netilmicin, tobramycin, and paromomycin.

In some embodiments, the antibiotic is selected from the groupconsisting of: mupirocin and gentamicin.

In some embodiments, the pyoderma gangrenosum is classic pyodermagangrenosum.

In some embodiments, the individual is experiencing an inflammatoryepisode of pyoderma gangrenosum.

In some embodiments, the individual has at least one ulcer located ontheir leg.

In some embodiments, the individual has at least one ulcer located ontheir hand.

In some embodiments, the pyoderma gangrenosum is selected from at leastone of the following: peristomal pyoderma gangrenosum, bullous pyodermagangrenosum, pustular pyoderma gangrenosum, and vegetative pyodermagangrenosum.

In some embodiments, the individual has at least one active pyodermagangrenosum ulcer.

In some embodiments, the individual has at least one active, non-healingpyoderma gangrenosum ulcer.

In some embodiments, the individual does not have inflammatory boweldisease.

In some embodiments, the individual does not have ulcerative colitis.

In some embodiments, the individual does not have Crohn's disease.

In some embodiments, Compound 1 is administered without food.

In some embodiments, the individual is administered the therapeuticallyeffective amount of Compound 1 once daily.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. Some embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et al.) While it is possible that,for use in the prophylaxis or treatment, a compound of the inventionmay, in an alternative use, be administered as a raw or pure chemical,it is preferable however to present the compound or active ingredient asa pharmaceutical formulation or composition further comprising apharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt, solvate, hydrate or derivative thereof together with one or morepharmaceutically acceptable carriers thereof and/or prophylacticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and not overlydeleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use; in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules orsuspensions, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a salt, solvate, hydrate orphysiologically functional derivative thereof can be used as activeingredients in pharmaceutical compositions, specifically as S1P1receptor modulators. The term “active ingredient” is defined in thecontext of a “pharmaceutical composition” and is intended to mean acomponent of a pharmaceutical composition that provides the primarypharmacological effect, as opposed to an “inactive ingredient” whichwould generally be recognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can vary andas is customary and known to the physician, it is to be tailored to theindividual conditions in each individual case. It depends, for example,on the nature and severity of the illness to be treated, on thecondition of the individual, on the compound employed or on whether anacute or chronic disease state is treated or prophylaxis is conducted oron whether further active compounds are administered in addition to thecompounds of the present invention. Representative doses of the presentinvention include, but are not limited to, about 1 mg to about 5 mg,about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg,about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg,about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg,about 4.75 mg, and about 5 mg. Multiple doses may be administered duringthe day, especially when relatively large amounts are deemed to beneeded, for example 2, 3 or 4 doses. Depending on the individual and asdeemed appropriate by the individual's physician or caregiver it may benecessary to deviate upward or downward from the doses described herein.

The amount of active ingredient or an active salt, solvate or hydratederivative thereof, required for use in treatment will vary not onlywith the particular salt selected but also with the route ofadministration, the nature of the condition being treated and the ageand condition of the individual and will ultimately be at the discretionof the attendant physician or clinician. Representative factors includethe type, age, weight, sex, diet and medical condition of theindividual, the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, whether an acuteor chronic disease state is being treated or prophylaxis is conducted orwhether further active compounds are administered in addition to thecompounds of the present invention and as part of a drug combination.The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety factors including those cited above. Thus, the actual dosageregimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimens outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, as 2,3, 4 or more sub-doses per day. The sub-dose itself may be furtherdivided, e.g., into a number of discrete loosely spaced administrations.The daily dose can be divided, especially when relatively large amountsare administered as deemed appropriate, into several, for example 2, 3or 4 part administrations. If appropriate, depending on individualbehavior, it may be necessary to deviate upward or downward from thedaily dose indicated.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the suitable pharmaceutically acceptable carrier canbe either solid, liquid or a mixture of both. Solid form preparationsinclude powders, tablets, pills, capsules, cachets, suppositories anddispersible granules. A solid carrier can be one or more substanceswhich may also act as diluents, flavoring agents, solubilizers,lubricants, suspending agents, binders, preservatives, tabletdisintegrating agents, or encapsulating materials.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesired shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet may befrom 0.5 to about 90 percent of the active compound. However, an artisanwould know when amounts outside of this range are necessary. Suitablecarriers for powders and tablets include magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein (e.g., by stirring). Themolten homogenous mixture is then poured into convenient sized molds,allowed to cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising the active agent in a flavored base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form.

In the latter case of a dropper or pipette, this may be achieved by theindividual administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols (e.g., nasal aerosols, by inhalation), this canbe carried out, for example, using a spray, a nebulizer, a pumpnebulizer, an inhalation apparatus, a metered inhaler or a dry powderinhaler. Pharmaceutical forms for administration of the compounds of thepresent invention as an aerosol can be prepared by processes well knownto the person skilled in the art. Solutions or dispersions of thecompounds of the present invention or a pharmaceutically acceptablesalt, solvate, hydrate or derivative thereof in water, water/alcoholmixtures or suitable saline solutions, for example, can be employedusing customary additives (e.g., benzyl alcohol or other suitablepreservatives), absorption enhancers for increasing the bioavailability,solubilizers, dispersants and others and, if appropriate, customarypropellants (e.g., carbon dioxide, CFCs, such as,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane and the like). The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively, the active ingredients may be provided in the form of adry powder (e.g., a powder mix of the compound in a suitable powder basesuch as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP)). Conveniently the powdercarrier will form a gel in the nasal cavity. The powder composition maybe presented in unit dose form (e.g., capsules, cartridges) as forgelatin or blister packs from which the powder may be administered bymeans of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

In some embodiments, the compositions are tablets or capsules for oraladministration.

In some embodiments, the compositions are liquids for intravenousadministration.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed by Berge et al., Journal ofPharmaceutical Sciences, 66:1-19 (1977), incorporated herein byreference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and that when administeredinto an individual undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1: Preparation of Compounds

The preparation of Compound 1, including certain crystal forms ofCompound 1 are described in International Patent Application No.PCT/US2009/004265, published as International Publication No.

WO2010/011316, and International Patent Application No.PCT/US2011/000153, published as International Publication No.WO2011/094008, the entire contents of each are incorporated herein byreference in their entirety.

The preparation of the crystalline free-plate habit of the non-solvatedL-arginine salt of Compound 1 is described in International PatentApplication No. PCT/US2016/038506, published as InternationalPublication No. WO2016/209809, the entire contents of which areincorporated herein by reference in their entirety.

Example 2: Clinical Trial for Skin Extra-Intestinal Manifestation (EIM)with Compound 1

A clinical trial is conducted in 10-20 individuals with IBD and activeskin extra-intestinal manifestations.

All visits in the study are ambulatory visits. A screening period of upto four weeks is followed by a 12-week treatment period. During thetreatment period, individuals take one 2 mg tablet of Compound 1 onceper day. The last dose is taken one day before the last treatment visitat week 12. A follow-up visit takes place two weeks after the end oftreatment (FIG. 1 ).

Screening Visit:

Individuals visit the study site for screening assessments up to fourweeks prior to the planned start of treatment.

Individuals start the 24-hour ambulatory pre-dose Holter (ECG)monitoring procedure at D-1.

Treatment Visits:

Visit (week 0, day 1):

Individuals return to the study site to receive the first dose ofCompound 1 and remain at the study site for six hours for safetyevaluation. Holter monitoring continues for another 18 hours.

Visits at week 1, week 2, week 4, week 8, and week 12:

Individuals return to the study site and undergo examinations at weeks1, 2, 4, 8, and 12. The last dose of Compound 1 is administered one daybefore the last treatment visit at week 12.

Follow up Visits/End of Study Visit:

Week 14 (two weeks after end of treatment):

Individuals return to the study site for the final visit.

Premature Discontinuation:

Procedures planned for week 14 are performed for all individuals thatdiscontinue the study prematurely.

Inclusion Criteria

1. Men or women of age 18 to 80 years, inclusive.

2. Able to give signed informed consent and willing and able to complywith the study requirements.

3. Considered to be in stable health in the opinion of the investigatoras determined by:

-   -   a.) A pre-study physical examination with no clinically        significant abnormalities unrelated to IBD.    -   b.) Vital signs (VS) at screening: pulse rate ≥55 bpm, systolic        blood pressure (SBP) ≥90, and diastolic blood pressure (DBP) ≥55        mmHg.    -   c.) Liver function tests (ALT/AST, bilirubin and alkaline        phosphatase)<2× the upper limit of normal [ULN].    -   d.) All other pre-study clinical laboratory findings within        normal range, or if outside of the normal range not deemed        clinically significant in the opinion of the investigator.    -   e.) 12-lead electrocardiogram (ECG) showing no clinically        significant abnormalities in the opinion of the investigator.    -   f.) A chest x-ray showing no evidence of active pulmonary        disease (a chest x-ray taken within the previous 12 months from        the screening visit may also be used).    -   g.) Ophthalmology evaluation (by an ophthalmologist) without        evidence of macular edema, supported with OCT where available        (dependent on site capability) no later than three months prior        to screening.

4. Individuals receiving stable treatment for IBD and ELM.

5. Diagnosis of active psoriasis, erythema nodosum or pyodermagangrenosum by physician assessments.

6. Diagnosis of ulcerative colitis (UC) or Crohn's disease (CD)established prior to screening by clinical and endoscopic evidence.

Permitted Medications for the Treatment of IBD (UC and CD)

Oral 5-ASA treatment is permitted for the treatment of IBD, providedthat the individual is receiving the medication(s) at baseline, and thatthe dose(s) has been stable. These medications are to remain stablethroughout the study.

Oral corticosteroids that the individual is receiving at baseline arecontinued, provided that the dose has been stable for two weeks prior tobaseline. These medications are to remain stable at least eight weeks.

TNF-alpha inhibitor treatment is permitted provided that the doseremains stable throughout the study.

Probiotics (e.g., Culturelle, Saccharomyces boulardii) are permittedprovided that the dose has been stable for the two weeks immediatelyprior to randomization.

Antidiarrheals are allowed throughout the study as necessary for controlof chronic diarrhea.

Azathioprine or 6-mercaptopurine are permitted, provided that the dosehas been stable for the eight weeks immediately prior to screening(these immunosuppressive agents are discontinued at the time ofrandomization).

Dermatological medications that the individual is receiving at baselineare continued, provided that these are stable for two weeks prior tobaseline and remain stable throughout the study.

Physician's Global Assessment (PGA) 1) Disease Activity Score for CD

Patient reported outcomes (liquid stools, abdominal pain and generalwellbeing) are captured in a daily diary by the individual. Patientreported outcomes can be reviewed by site personnel during screening and(prior to dosing, if applicable) at weeks 0, 1, 2, 4, 8 and 12 and atany unscheduled visit(s) due to disease exacerbation. Presence ofextra-intestinal manifestation (arthritis/anthralgia, iritis/uveitis,skin/mouth lesion, peri-anal disease, other fistula, fever >37.8° C.),use of anti-diarrheals, abdominal mass, haematocrit and weight arecaptured weekly or at each visit. The investigator or designeecalculates the disease activity scores taking into consideration theabove data and the individual reported outcomes.

2) Physician Global Assessments for Active Skin Extra-IntestinalManifestations

The Physician Global Assessment (PGA) is used as an instrument tomeasure skin disease activity (e.g., for EG, EN or psoriasis).

Patients Global Assessment for active skin extra-intestinalmanifestations.

The Patients Global Assessment will be used to measure how individualsrate the severity and pain of their skin disease.

3) Dermatology Life Quality Index (DLQI)

This questionnaire measures how much of the individual's life isaffected by their skin problems.

4) Psoriasis Area and Severity Index (PASI)

The PASI is a tool for the measurement of severity of psoriasis. PASIcombines the assessment of the severity of lesions and the area affectedinto a single score in the range 0 (no disease) to 72 (maximum disease).

5) Inflammatory Bowel Disease Questionnaire (IBDQ)

The IBDQ is used to measure how the individual has felt during the lasttwo weeks. The IBDQ is used during screening and at weeks 2, 4, 8, and12.

6) Skin Punch Biopsies

Skin punch biopsies (from healthy skin and from target lesion) arecollected before treatment and at week 8 or 12. Immunohistochemistry andother analysis methods (such as RT-PCR) are performed to evaluate immunecell infiltration, cytokine expression in the skin and otherinflammatory parameters.

7) C-reactive Protein (CRP)

Blood samples for analysis of C-reactive protein (CRP) are collected atscreening; at weeks 0, 1, 2, 4, 8, and 12; and at the two-weekfollow-up.

Efficacy Endpoints

-   -   UC endpoint: Change from baseline in stool frequency, rectal        bleeding, PGA (Physicians Global Assessments) at weeks 1, 2, 4,        8 and 12.    -   CD endpoint: Change from baseline in disease activity score at        week 1, 2, 4, 8 and 12.    -   Change from baseline in endoscopic improvement/histologic        healing using endoscopy or flexible proctosigmoidoscopy (only if        there are signs of inflammation at screening another evaluation        is performed at week 12).    -   Change from baseline in level of fecal calprotectin at week 4, 8        and 12. Change from baseline in Physician Global Assessments for        active skin extra-intestinal manifestations (PG, EN and        psoriasis) at week 1, 2, 4, 8 and 12.    -   Change from baseline in Patients Global Assessments for active        skin extra-intestinal manifestations (PG, EN and psoriasis) at        week 1, 2, 4, 8 and 12.    -   Change from baseline in the Dermatology Life Quality Index        (DLQI) score at week 1, 2, 4, 8 and 12.    -   Psoriasis endpoint only (all other endpoints are for all skin        manifestations): Change from baseline in Psoriasis Area and        Severity Index (PASI) score at week 1, 2, 4, 8 and 12.    -   Change from baseline in Inflammatory Bowel Disease Questionnaire        (IBDQ) score at week 2, 4, 8 and 12.    -   Skin punch biopsies (from healthy skin and from target lesion)        are collected before treatment and at week 8 or 12.        Immunohistochemistry and other analyzing methods such as RT-PCR        are performed to evaluate immune cell infiltration, cytokine        expression in the skin and other inflammatory parameters.    -   Change from baseline in C-reactive protein (CRP) at weeks 1, 2,        4, 8 and 12.    -   Change from baseline in leucocyte characterization.    -   Change from baseline in lymphocyte counts at weeks 1, 2, 4, 8        and 12.

Example 3: Clinical Trial for Pyoderma Gangrenosum with Compound 1

A clinical trial is conducted in individuals aged 18 to 80 years old(inclusive) who have active pyoderma gangrenosum (PG) ulcers. All visitsin the study are ambulatory visits. The screening period lasts up tofour weeks and is followed by a 12-week treatment period. During thetreatment period, individuals take one 2 mg tablet of Compound 1 onceper day. The last dose is taken one day before the end of the treatmentperiod (week 12). A follow-up visit takes place two weeks after the endof treatment.

Screening Visit

Each individual visits the study site for screening assessment within 4weeks of the planned start of the treatment (Day 1). Individuals thenundergo screening procedures to determine eligibility.

Individuals return to the study site at Day-1 for confirmation ofeligibility, and start the 24-hour ambulatory pre-dose Holter (ECG)monitoring procedure.

Treatment Visits

Baseline Visit (Day 1): Individuals return to the study site to receivethe first dose of Compound 1. Individuals are instructed to take thetablet first thing in the morning on an empty stomach. Individuals areadvised not to crush, break, chew, or dissolve the tablet and to takestudy medication with an adequate amount of water. The individualsremain at the study site for at least six hours for safety evaluation.Holter monitoring continues to allow for an overall continuous 24-hourpre- and a 24-hour post-dose monitoring.

Visits at week 2, week 4, week 8, and week 12: Individuals return to thestudy site and tests are conducted. The last dose of Compound 1 isplanned 1 day before the end of the treatment visit at week 12.

Follow up Visit/End of Study Visit

Visit at week 14 (two weeks after end of treatment): Individuals returnto the study site for the final visit.

Permitted Medications

Oral corticosteroids

TNF-alpha inhibitor (etanercept, infliximab, adalimumab or other)

Oral 5-ASA medication

Antidiarrheal treatment

OTC analgesics (paracetamol/acetaminophen, NSAIDs)

Efficacy Endpoints

Change from baseline (Day 1 pre-dose) to week 12 in Physician GlobalAssessments for active skin manifestations. Assessment of targetlesion/ulceration:

-   -   0: Total resolution of target ulcer with no signs of active PG    -   1: Almost completely healed target ulcer with only minimal signs        of active PG    -   2: Evidence of target ulcer healing which involves at least 50%        of ulcer/ulcer margin    -   3: Evidence of target ulcer healing which involves less than 50%        of ulcer/ulcer margin    -   4: No evidence of target ulcer healing

Change from baseline (Day 1 pre-dose) to week 12 in Patient GlobalAssessments for active skin manifestations: visual analog scale (VAS)for assessment of severity of the disease and severity of pain bypatient.

Change from baseline (Day 1 pre-dose) to week 12 in Dermatology LifeQuality Index (DLQI).

Change from baseline (Day 1 pre-dose) to week 12 in CRP levels.

The Following Measures are Also Assessed:

Imaging (digital photos) of the target lesion.

Evaluation of the changes in surface area of target lesion.

Punch biopsy (histology).

Example 4: BET (Brunauer, Emmett, and Teller) Specific Surface AreaMethod (Plate Habit)

In general, the specific surface areas for crystalline free-plate habitof the non-solvated L-arginine salt of Compound 1 were determined byphysical adsorption of nitrogen gas on the surface of the sample fromeach lot using the well-established technique based on the Brunauer,Emmett, and Teller theory.

The BET surface areas for the samples were measured by MicromeriticsPharmaceutical Services using a Micromeritics™ TriStar II BET surfacearea analyzer (MicroActive for TriStar II Plus 2.02 Software™). Thesamples were degassed at 25° C. for 960 minutes under vacuum (i.e., 100mm/Hg). The determination of the adsorption of N₂ at 77.3 K was measuredusing a BET surface area eleven-point method with relative pressures inthe range of about 0.05 to about 0.3 (P/P₀) for a weighed amount of eachsample, see Table 1 below. The analysis was performed per IS09277.

TABLE 1 Correlation BET Surface Arena Lot Lot Number Sample (g)Coefficient Area (m²/g) 5015-12-12 A1 0.6163 0.99916 0.7 5015-12-13 A21.5270 0.99945 0.7 5015-12-14 A3 0.4465 0.99922 1.5 5015-12-15 A4 0.57090.99939 1.0 5015-12-16 A5 0.9582 0.99940 0.8 04GSp A6 0.4332 0.99921 2.405GSp A7 0.3652 0.99910 1.9 06GSp A8 0.6866 0.99984 3.0 07GSp A9 0.27540.99914 3.1

Example 5: Formulations for L-Arginine Salt of(R)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)-benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticAcid

Core tablets were manufactured using the formulation as described inTable 2 and using substantially the same process as described in FIG. 4. The L-arginine salt of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid is 72.42% free acid (Compound 1) and 27.58% L-arginine (i.e., 1.381mg of the L-arginine salt of Compound 1 corresponds to 1 mg ofactive/free acid).

TABLE 2 Tablet Strength 1 mg 2 mg L-Arg Salt of Compound 1 1.381 2.762Mannitol Pearlitol ® 100SD 54.119 52.738 Microcrystalline cellulose -Avicel ® 40 40 Sodium Starch Glycolate - Explotab ® 4 4 MagnesiumStearate 0.5 0.5 Opadry ® II Blue 4 4 Total tablet target weight 104 104

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention.

1. A method of treating pyoderma gangrenosum (PG) in an individual inneed thereof, comprising administering a therapeutically effectiveamount of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, wherein the Compound 1, or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof, is an L-arginine salt ofCompound
 1. 2. (canceled)
 3. (canceled)
 4. (canceled)
 5. The methodaccording to claim 1, further comprising administering the L-argininesalt of Compound 1 in combination with a therapeutically effectiveamount of a corticosteroid selected from the group consisting ofdexamethasone, hydrocortisone, methylprednisolone, prednisolone,prednisone, triamcinolone, and fludrocortisone.
 6. (canceled) 7.(canceled)
 8. (canceled)
 9. (canceled)
 10. (canceled)
 11. (canceled) 12.The method according to claim 1, wherein the PG is an active PG. 13.(canceled)
 14. (canceled)
 15. The method according to claim 1, whereinthe individual has at least one condition selected from the groupconsisting of an inflammatory bowel disease, arthritis, a hematologicaldisease, and an autoinflammatory disease.
 16. The method according toclaim 1, wherein the individual has at least one condition selected fromthe group consisting of ulcerative colitis and Crohn's disease. 17.(canceled)
 18. (canceled)
 19. (canceled)
 20. The method according toclaim 1, further comprising administering the L-arginine salt ofCompound 1 in combination with a therapeutically effective amount of acompound selected from the group consisting of a corticosteroid, animmunosuppressant, a biologic, an anti-inflammatory agent, and anantibiotic.
 21. (canceled)
 22. (canceled)
 23. (canceled)
 24. (canceled)25. (canceled)
 26. (canceled)
 27. (canceled)
 28. The method according toclaim 1, wherein the pyoderma gangrenosum is classic pyodermagangrenosum.
 29. The method according to claim 1, wherein the individualis experiencing an inflammatory episode of pyoderma gangrenosum. 30.(canceled)
 31. (canceled)
 32. The method according to claim 1, whereinthe pyoderma gangrenosum is selected from at least one of the following:peristomal pyoderma gangrenosum, bullous pyoderma gangrenosum, pustularpyoderma gangrenosum, and vegetative pyoderma gangrenosum.
 33. Themethod according to claim 1, wherein the individual has at least oneactive pyoderma gangrenosum ulcer.
 34. The method according to claim 1,wherein the individual has at least one active, non-healing pyodermagangrenosum ulcer.
 35. The method according to claim 1, wherein theindividual does not have inflammatory bowel disease.
 36. The methodaccording to claim 1, wherein the individual does not have ulcerativecolitis.
 37. The method according to claim 1, wherein the individualdoes not have Crohn's disease.
 38. The method according to claim 1,wherein the L-arginine salt of Compound 1 is in an amount equivalent toabout 1 mg to about 5 mg of Compound
 1. 39. (canceled)
 40. (canceled)41. (canceled)
 42. (canceled)
 43. (canceled)
 44. The method according toclaim 1, wherein the L-arginine salt of Compound 1 is an anhydrous,non-solvated crystalline form of the L-arginine salt of Compound
 1. 45.The method according to claim 1, wherein the L-arginine salt of Compound1 is a crystalline free-plate habit of the non-solvated L-arginine saltof Compound
 1. 46. (canceled)
 47. The method according to claim 1,wherein the L-arginine salt of Compound 1 is administered orally. 48.(canceled)
 49. The method according to claim 1, wherein the L-argininesalt of Compound 1 is administered once daily.
 50. (canceled)
 51. Amethod of treating pyoderma gangrenosum (PG) in an individual in needthereof comprising administering a therapeutically effective amount of(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)aceticacid (Compound 1), or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, in an amount equivalent to about 1 mg to about 5 mg ofCompound
 1. 52. The method according to claim 51, wherein the Compound1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof,is in an amount equivalent to about 1 mg to about 2 mg.
 53. The methodaccording to claim 51, wherein the Compound 1, or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof, is in an amount equivalentto about 1 mg of Compound
 1. 54. The method according to claim 51,wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate,or solvate thereof, is in an amount equivalent to about 2 mg of Compound1.